This application addresses how cone photoreceptors are specified in the mammalian retina and how the cells are organized across the retinal surface. Cone photoreceptors provide the principal sensory input for human vision. These cells endow other vertebrates and us with color vision by expressing specific visual pigments that absorb different wavelengths of light. The loss of these cells in macular degeneration and other forms of retinal degenerations are major causes of blindness. The long-term objectives of our work are to define the programs and molecular mechanisms that specify the development of cone cells and their topographical organization in the retina. In defining these mechanisms we seek to identify intrinsic factors that maintain the cells in health. This information is needed to devise therapy to prevent cone loss and to attempt repair of the damaged retina. The proposed studies will be carried out in the mouse to take advantage of molecular genetics and transgenic animals in which cells are marked or programs are genetically manipulated. The application is built on our observations that most cones in the mouse retina co-express both S (UV/blue) and M (green) opsin, but different temporal and spatial mechanisms regulate the expression of these opsins. One factor that controls the expression of M opsin and affects the patterning of S opsin is a thyroid nuclear hormone receptor isoform. Little is known about thyroid receptors and thyroid hormone in the retina. Thus, we propose (1) to specify the temporal and spatial expression of the S and M opsins during development; (2) to explore the role of thyroid hormone and receptors in the retina; (3) to identify thyroid receptor mechanisms that control M opsin expression; and (4) to explore mechanisms that control the spatial expression of S opsin.